This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. SIV infection in rhesus macaques of Chinese origin (Ch Rh) results in high frequency (30%) of long-term nonprogressing macaques which is a markedly larger incidence than can be found in HIV-1 infected humans or SIV-infected macaques of Indian origin ( 5%). We use this unique model for investigating the role of natural killer cells in the establishment of long-term nonprogressing state in LTNP Ch Rh, which could provide direct implications/guidance for vaccine design to combat HIV-1 infection. These LTNP animals have high peak viremia indistinguishable from progressing Ch Rh or Ind Rh, indicating that this is not due to inherent viral resistance, but more likely, that immune responses are responsible for the ultimate control of viral replication. Thus far, we found that neither neutralizing antibodies nor T-cell immune responses are clearly correlated with long-term nonprogression. Interestingly, in the study of innate immunity and NK cell responses, we found that NK cells had different levels of turnover between LTNP and NP during acute SIV infection;NK cells were potent killers through mechanisms of both cytotoxicity and release of antiviral cytokines by different NK subsets. We also found that high SIV-specific non-NAb responses were elicited, which may be related to NK cell-mediated antibody-dependent cell-mediated cytotoxicity (ADCC). Our data demonstrate that NK cells may play an important role in protection from disease. By manipulating NK cells and function to resist infection, new generation of vaccine development may be plausible for controlling infection under an aviremic long term nonprogressive state which will prolong AIDS-free survival and will possibly reduce viral transmission in a population level.